Tumors consist of a collection of cells that demonstrate autonomous hyperplasia. Although they are categorized as malignant tumors (or so-called cancers), which have the potential of causing death of the tumor-laden animal, and benign tumors, which do not have such potential, there are numerous exceptions and it is difficult to strictly distinguish between the two (Iwanami Biology Encyclopedia, 3rd Edition, page 4).
The three pillars of current cancer therapy consist of surgical therapy, chemotherapy and radiotherapy, and more realistically, multidisciplinary therapy that combines the above treatments with laser therapy and so on is widely performed. In consideration of the pain associated with therapy and metastasis, it is only natural to place considerable expectations on chemotherapy, and although numerous antitumor agents have been developed and are used to respond to these expectations, none are effective against all tumors. In addition, many antitumor agents are unable to demonstrate adequate effects when used alone or cannot be used for an extended period of time due to severe adverse side effects, and multiple agents are typically used in combination. Thus, there are considerable expectations being placed on the development of a new antitumor agent, and particularly that which has potent anticancer effects and which can be used for an extended period of time by a simple method.
Anticancer agents that are effective against brain tumors in particular have yet to be discovered. According to the Guidelines for the Treatment of Brain Tumors (Kanehara & Co., Ltd., published on Jul. 31, 2002), the total number of cases of brain tumors from 1969 to 1993 exceeded 81,000, and the approximate number of affected persons is estimated to be about 8 to 10 per 100,000 persons.
Primary brain tumors are classified into more than 10 types according to their origin of onset and pathological tissue type, examples of which include glioma and meningioma. Gliomas are particularly serious in terms of both incidence and malignancy, and are classified into seven or more types such as glioblastoma and anaplastic astrocytoma according to their detailed pathological tissue type. Disease stage (tumor size, presence of distal metastasis) and histological malignancy are used when determining the degree of malignancy of primary brain tumors. Histological malignancy is classified into four levels consisting of G1 to G4 according to the Guidelines for the Treatment of Brain Tumors (op cit.), and these correspond to WHO1 to WHO4, respectively. The larger the number, the higher the degree of malignancy. For example, the malignancy of glioblastoma is G4 (WHO4), while the malignancy of anaplastic astrocytoma is G3 (WHO3), and both G3 and G4 are classified as malignant. Thus, those primary brain tumors that should first be targeted by anti-brain tumor agents are gliomas, and particularly glioblastoma or anaplastic astrocytoma associated with a high degree of malignancy.
Gliomas are tumors that occur in the brain parenchyma and demonstrate invasive growth, and it is difficult to achieve a complete cure with surgery alone. Glioblastomas in particular are the most resistant to treatment, and have an extremely poor five-year survival rate of about 8%. Although definitive efficacy of chemotherapy has only been confirmed for alkylating agents and temozolomide, their efficacy is limited to concomitant use with radiotherapy. On the other hand, post-surgical radiotherapy has been recognized to demonstrate life-prolonging effects.
TNF-α has been previously reported to have a certain degree of antitumor effects against brain tumors when used in special forms of therapy. For example, antitumor effects have been reported to be obtained against glioblastoma during local injection of TNF-α (Hayashi, S. et al.: Clinical significance of the expression of nuclear factor-kappa B, tumor necrosis factor receptor type I (TNFR I, and c-mycin in human malignant astrocytomas”, Neurol. Med. Chir., 2001, Vol. 41, pp. 187-195), and a certain degree of antitumor effects have been reported to be obtained following intra-arterial injection of TNF-α (Harada, K. et al.: “Antitumor effect of intra-arterial tumor necrosis factor-alpha in rats with transplanted intracerebral glioma and its evaluation by MRI”, Japan J. Neurosurgery, 1995, Vol. 23, pp. 1069-1074).
However, in the case of administration of TNF-α, even if antitumor effects are obtained, there is the problem of these effects not leading to life-prolonging effects, and there are in fact no reports describing the obtaining of life-prolonging effects in brain tumor patients administered TNF-α. In addition, life-prolonging effects have also not been observed in glioblastoma rats administered TNF-α.
On the other hand, although polypeptides represented by X—X′—(amino acid sequence of the fourth exon portion of TNF) (wherein, X represents a single hydrogen atom or a peptide for which the type and number can be determined arbitrarily, X′ represents a peptide having 1 to 39 amino acid residues, and the ratio of the number of net basic amino acid residues to the number of amino acid residues that compose X and X′ exceeds 14.5%) (Japanese Patent No. 2544114), and polypeptides composed of the amino acid sequence described in SEQ. ID NO. 1 or 2 (Japanese Patent Publication No. H8-17716) are known to have antitumor action, these polypeptides are not known to have malignant glioma antitumor action.